3d fabrication of needle tip geometry and knife blade

ABSTRACT

The present invention provides a method for creating a beveled needle or a blade. The method employs a side wall surface of an angled post as a base to control beveled tip geometry. The invention provides needles, microneedle arrays, blades and microblade arrays with sufficient sharpness and toughness.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.11/818,622, filed on Jun. 14, 2007 and entitled “3D FABRICATION OFNEEDLE TIP GEOMETRY AND KNIFE BLADE,” now allowed, which applicationclaims the benefit of and priority to U.S. Provisional Application Ser.No. 60/830,307, filed on Jul. 12, 2006, entitled “3D FABRICATION OFNEEDLE TIP GEOMETRY AND KNIFE BLADE,” the entirety of each of which areincorporated herein by reference.

TECHNICAL FIELD

The invention relates to the field of device fabrication, such as,fabrication and manufacture of microneedles or microblades.

BACKGROUND

Various forms of drug delivery systems, such as patches, capsules, andneedles, are known in the art to administer drugs to a subject. Variousmethods of extracting blood samples, for example, making a small cutwith a blade, are also available. Among the current drug deliverysystems and methods of extracting blood samples, a hypodermic needle iscommonly used, and is known as one of the most effective devices.

However, using a conventional hypodermic needle has severaldisadvantages. For example, penetration of skin using a conventionalhypodermic needle may cause pain to a subject. Also, mishandling of aconventional hypodermic needle may result in infections caused by humanimmunodeficiency virus (HIV), hepatitis B and C viruses, etc.^([1-6])Hence, many researchers have been developing hypodermic needles in smallscale referred to as “microneedles,” to administer drugs or extractblood.

Employing diffusion effects, a microneedle can deliver a drug throughthe skin without deep penetration. Skin thickness varies depending onits location. Normally, human skin comprises three layers: stratumcorneum, viable epidermis, and dermis. A microneedle can penetrate thefirst two layers of the human skin, which is about 150 μm, to deliver adrug effectively. For collecting blood samples from a human, the lengthof a microneedle should be in the range of about 500 μm.

Usually, three different materials are used for creating a hollowmicroneedle: silicon-based material including glass, metal, andphotosensitive polymers. McAllister et al. developed a hollowmicroneedle based on silicon dioxide (SiO₂), in out of plane and lateralfashion, using a heavy chemical etching process.^([7-8]) Stoeber et al.also applied a similar fabrication process to create a hollowmicroneedle.^([9]) Both McAllister et al. and Stoeber et al. used bulkmicromachining technology to create the outer microneedle geometry, andused deep reactive ion etching (DRIE) or reactive ion etching (RIE) tocreate the hollow geometry. First, the process begins with the hollowholes created by the RIE technique followed by growing silicon dioxidethermally which will later become a needle structure. Machined Pyrex® isthen anodically bonded to a silicon wafer to create a space forreservoir. At last, the silicon wafer is etched back withtetramethylammonium hydroxide to define the height of the needle. Forlateral microneedles, it is fabricated by using a surface micromachiningtechnique. A patterned silicon dioxide layer defines microchannels, anda nitride layer is deposited to create the top and side walls. Multipleethylendiamminepyrocatechol (EDP) etches are carried out to complete theprocess.

Brazzle et al. created a metallic microneedle in a lateral fashion usingsurface micromachining technique.^([10-11]) The sequence ofphotolithography is carried out for patterning silicon nitride (Si₃N4)on a heavily doped silicon substrate and etched in potassium hydroxide(KOH) to build a platform for the microneedle. Palladium is thenelectroplated on the patterned area to define the bottom wall followedby spinning a layer of photoresist. A 20 μm thick photoresist ispatterned and developed to form the shape of the inside of the needle.Further electroplating is performed to build the side walls and top wallfor encapsulating the photoresist. Finally, the photoresist is etched toleave a hollow metallic microneedle. McAllister et al. also manufactureda metallic microneedle array, which has square cross-section channel,using similar procedures. The base layer is electroplated followed bydepositing and patterning a sacrificial thick photoresist. A seed layeris then sputtered onto the photoresist. Next, the side and top walls areelectroplated. Finally, the photoresist is removed and the needlestructure is lifted from the substrate.

A more realistic, out of plane, microneedle array has been developed byKim et al. using a tapered negative photoresist (SU-8).^([12]) Thetapered SU-8 post, which has angles between 3.1 to 5 degrees, is createdusing backside exposure on top of the SU-8 block which functions as abase. The seed layers are deposited, and electroplating is carried outto obtain 200 μm and 400 μm in length and thickness of 10 μm and 20 μm,respectively.

Moon et al. presented a different approach of microneedle fabricationusing a deep X-ray to create an inclined polymericmicroneedle.^([13-14]) The fabrication process begins with exposingpolymethylemetacrylate (PMMA), a positive photoresist, under X-rayvertically followed by successive exposure in a pre-defined anglewithout moving the substrate. These two steps define a sharp needle tipat the region of interception of the exposures. A sharp tip angle below40 degree is achieved with the needle length of between 600 μm to 1000μm.

Kuo et al. reported fabrication of polymeric microneedles usingSU-8.^([15]) A trapezoidal trench is created by potassium hydroxide(KOH) etch on 100 silicon wafer. The angle of the trench (about 35.3degrees: measured from the vertical to the etched surface) is used todetermine the angle of the beveled tip of a microneedle. After KOHetching is used to obtain the trapezoidal grooves, SU-8 is then appliedand patterned using lithographic technique to create an array of hollowneedle structures. Partial SU-8 development is carried out to expose theends of the microneedle structure. These partially exposed needlestructures are covered with another layer of SU-8 to form the base. Thesecond SU-8 layer is further patterned and developed. The length of themicroneedle is about 600 μm. A negative mold is also replicated withpolydimethylesiloxane (PDMS). The report shows that these needles cansuccessfully penetrate skin.

However, silicon-based microneedle structures tend to be brittle.Stiffness and toughness of metallic microneedles are still in questiondue to their thin walls. Flat needle tips of these metallic microneedlesare not suitable for skin penetration. For microneedles made ofphotosensitive polymer, the stiffness of the needle structures and thestrength between the needle structures and the bases are uncertain, eventhough the needles are capable of skin penetration.

Sparks et al. developed a microneedle array with sharp beveled tipsusing combinations of LIGA and soft lithography technique.^([24]) Twodimensional sawtooth profile was patterned on polymethylmethacrylate(PMMA) to create the beveled tip microneedle using Deep x-raylithography (DXRL). The angle of the sawtooth design becomes the beveledangle of the final microneedle tip. The four different angles weretested from 25 to 40 degrees. The sawtooth structure is then cut inpieces, stacked on top of each other piece, turned, and the side wallwas glued on a conductive substrate to form a 8×10 mm area formicroneedle array. The second radiation performed on a glass slab tocreate a mask patterned of equilateral triangles with a hole pattern fordefining the microneedle and the hollow features directly on thesawtooth structure. After exposure and partial development of the PMMAsubstrate, electroplating was carried out to form the metal layer aroundthe needle structures. The thickness of the metal layer provides spacefor creating a base of the microneedle array. A successive developmentof the microneedle opens the bottom of the hollow features. Next,polyvinyl alcohol (PVA) is cast onto the microneedle array and used as asacrificial template to replicate the microneedle array consisted ofPMMA (material for actual microneedle structure) and a metal (for abase). Finally, PMMA is cast on the replicated PVA mold. Dissolving thePVA mold in water reveals the final product of plastic microneedlearray. Advantage of the technique described above is that use of moldingprocess opens the possibility of mass production for the beveled plasticmicroneedle array. The difficulty in assembly of sawtooth structure fromthe 2½ D in order to create 3D inclined structure, and in alignment ofsecond radiation to create hollow features on the needle structure aswell as use of expensive DXRL technique become disadvantages.

Perennes et al. created microneedle arrays and blades in plane by meansof etching the patterned single crystal silicon.^([25]) First, thepatterned single crystal silicon is etched to form the microchannelswhich will become the hollow structure in the needle. Second, fusionbonding of silicon to silicon is performed to seal the etchedmicrochannels. Next, the plasma etching is carried out around theembedded microchannels according to the 2D beveled needle layout. Atlast, anisotropic etching creates the microneedle with the vertical sidewall as well as it opens the microchannel on the side of the beveledsurface along the vertical wall. In addition, the fabrication ofmicroblade uses same manufacturing steps excluding creatingmicrochannels and fusion bonding process. This technique can producecontrollable 2½ D in plane microneedle arrays and microblades. However,the material used in the experiment is brittle and the cutter length ofthe blade is too short.

Although many microneedle fabrication processes have been developed, andthere is a steady growth of using microneedles, the majority of thebiomedical industry is still reluctant to adopt various microneedlefabrication techniques for needle production. A good needle structureshould meet at least the following criteria: (1) adequate stiffness toprevent premature buckling failure, (2) adequate sharpness to penetratea rubber-like skin, (3) adequate toughness to avoid particle breakagewhich may clog the vein, (4) sufficiency in length for use as a drugdelivery or a body fluid extracting device, and (5) adequatebiocompatibility.

SUMMARY OF THE INVENTION

Provided is, among other things, a method for preparing a needle with orwithout a hollow section, a needle array, a blade, or a blade array, themethod comprising: creating at least one inclined or skewed structurethat defines the angle of the needle or blade tip. The inclinedstructure can be created by various techniques including but are notlimited to mechanical machining, laser ablation, lithography, abrasion,electric discharged machining (EDM), electric chemical machining (ECM)and etching. Multiple exposures can be used for creating the inclinedstructure. A needle or blade mold structure or an actual needle or bladestructure can be built upon the inclined structure.

In certain embodiments, provided is a mold structure for a needle, aneedle array, a blade or a blade array. The mold structure is built uponat least one inclined structure, which controls the angle and thus thesharpness of the needle or blade. Various materials, such as metal,plastic, polymer, and/or biocompatible materials, can be deposited ontoa mold structure to create a needle, a needle array, a blade or a bladearray for a specific application.

In certain embodiments, also provided are devices including needles,blades, microneedle arrays, and microblade arrays, wherein the sharpnessof the needle or blade is controlled by at least one inclined structure.The device provided by the invention can be of any size, in eitherlength or diameter, and/or of various shapes.

DESCRIPTION OF THE FIGURES

FIG. 1: A schematic of light angles traveling through a limestone glasssubstrate. Θ₁ and Θ₂ are incident angles for the glass substrate andSU-8. Θ₃ is the refractive angle in SU-8.

FIG. 2: An array of skewed posts.

FIG. 3: A schematic of a microneedle manufacturing process: a) a glasssubstrate, b) metal layer deposition, c) a positive photoresistdeposition, d) patterning the photoresist for etching the metal layer,e) spin-coating SU-8 photoresist, f) back-side exposure to create tiltedposts, g) spin-coating SU-8 and patterning for needle mold structures,h) developing but not post-exposure bake, i) spin-coating another SU-8layer for extending post and creating a base, j) developing andperforming post-exposure bake, k) depositing a seed layer, l) nickelelectroplating, and m) CMP to open the end of the needle base and removeSU-8.

FIG. 4: An example of inside structures of wells.

FIG. 5: An array of wells before electroplating.

FIG. 6: A picture showing posts used for creating hollow structuresduring electroplating for a microneedle array.

FIG. 7: The front view of a beveled metallic microneedle.

FIG. 8: An angled view of a beveled metallic microneedle.

FIG. 9: A round microneedle post with a flat tip.

FIG. 10: An angled view of round microneedle post array.

FIG. 11: A backside view at 45 degree angle of round microneedle post.

FIG. 12: Various cross sections of a blade or a mold and a side view ofa needle structure or mold.

FIG. 13: One design for creating microneedle and microneedle moldstructures.

FIG. 14: One design for tapered microneedle and microneedle moldstructures.

FIG. 15: Designs for blade and blade mold structures.

FIG. 16: One design for a die cutter.

DETAILED DESCRIPTION OF THE INVENTION

A beveled metallic needle is developed using a three-dimensional (“3D”)SU-8 mold structure. Microneedle array with controllable beveled angleof the needle tip in metal, plastic and other materials can also bemade. The 3D mold is fabricated using an angled exposure onto the SU-8to create a skewed surface which will become a beveled surface followedby a series of vertical exposures to create wells which will then becomeneedle posts. Development of various depths with a single exposure is acrucial factor for creating a mold structure with a beveled surface.Similar fabrication procedures can be adopted to create a blade ormicro-blade. The invention provides complex design for controllable 3Dtip geometry.

Existing microneedle fabrication techniques cannot control the needletip geometry in 3D. Some existing techniques can produce an angledneedle. However, the present invention offers far more flexibilities.For example, the present invention can provide a tubular hollow needlewith an angled tip. The present invention can also provide controlledsharp needle tip or other 3D geometries for various purposes such aseasy penetration for drug delivery, blood and/or cell extraction, cellmanipulation or transfer, etc. A 3D knife blade with controlled bladecan also be created for microsurgical applications. The fabrication canbe carried out in either a vertical or a horizontal layout.

In one aspect, the invention provides a method for preparing a needlewith or without a hollow section, a needle array, a blade or a bladearray, the method comprising: creating at least one inclined or skewedstructure that defines the angle of the needle or blade tip. Theinclined structure can be created by various techniques including butare not limited to mechanical machining, laser ablation, lithography,abrasion, electric discharged machining (EDM), electric chemicalmachining (ECM), and etching. Multiple exposures can be used forcreating the inclined structure. The inclined structure can be made ofvarious materials. A mold structure or an actual needle (array) or blade(array) structure can be built upon the inclined structure.

In one embodiment, the mold structure comprises a well with a postinside the well, which well defines a part of the needle wall, and whichpost defines a part of the hollow section of the needle. A layer ofmaterial deposited upon the mold structure becomes a part of the needlewall. A specific example of the present invention is illustrated in FIG.3 (a) through (m). The present embodiment should be deemed more generalthan illustrated in FIG. 3. In another embodiment, the mold structurecomprises a well without a post inside, applying a layer of materialupon the mold structure results in a needle without a hollow section, ora blade.

It is to be noted, the masks for patterning a needle or blade (mold)structure, as exemplified in FIG. 3( g), can be of various shapes, suchas oval, square or diamond. Using different shaped masks thus producesneedles or blades of various cross sections, as exemplified in FIG. 12.In order to function as a blade effectively, the cross section of themold is more likely stretched in one direction than the other. In aparticular embodiment, a gray scale mask, as exemplified in FIG. 14( d),is used to create a tapered needle or blade structure. A gray scale canalso be used for controlling or varying exposure dosage of lightsources.

The inclined structure or inclined post that defines the angle of aneedle or blade tip can be built upon a substrate. The inclined post mayhave various angles relative to the substrate, thus providing a needleor blade tip with various angles, and thus providing a needle or bladetip with varying sharpness. A more skewed post will provide a flatterneedle tip. A skewed post is exemplified in FIG. 3 (f). The post can bemade of a photoresist material. For example, a negative photoresist suchas SU-8 is deposited onto a substrate. The backside of the substrate isexposed under UV light at a desired angle, and then the SU-8 layer isdeveloped in an appropriate bath. The angle of the post relative to thesubstrate is defined by the direction of the UV irradiation. Suchdeposition, irradiation and development techniques of photoresist arecommonly known in the art of lithography or photolithography. Morespecifically, a post-exposure bake can be performed. After developmentof the photoresist layer, a rinse step, e.g., rinsing with isopropylalcohol, can be applied to check the degree of development and removeuncrosslinked photoresist. Treatment procedures of photoresist such asbaking or rinsing are also known in the art. It is also known in the artthat photoresist can be patterned by other light sources such as laserand X-ray. A point light source, e.g., laser, can be used to irradiate,at a defined angle, a defined area, as exemplified in FIG. 16.

The substrate, which the inclined post is built upon, can be transparentto a light source. For example, the substrate can be glass or plastic.In one embodiment, a UV-transparent substrate is coated with a non-UVtransparent material, such as a metal layer, e.g., chromium. The coatedsubstrate is patterned to create areas that are UV transparent.Patterning of the coated substrate can be facilitated by a layer ofphotoresist. Patterning techniques of a substrate or a photoresist layerare known in the art, and are exemplified as follows. A positivephotoresist, such as AZ 1518, is deposited onto a metal-coatedsubstrate. The substrate is baked and exposed to UV light under apatterned mask. The patterned photoresist is developed, and then thesurface of the metal-coated substrate is etched to define a mask to beused for creating an inclined post that defines the tip angle of aneedle. An example of patterning a metal-coated substrate is illustratedin FIG. 3 (a) through (d). In another embodiment, when a UV-transparentsubstrate is used, a patterned mask can be placed under the substrate tofacilitate UV exposure from the backside, and thus coating of thesubstrate with a non-UV transparent material is not necessary.

However, the substrate needs not to be transparent to a light source.For example, one can expose a photoresist layer deposited on a substratefrom the top with a light source set at an appropriate angle to producean inclined post, as exemplified in FIG. 14 (a).

It should be appreciated, in various embodiments of the invention, whena certain structure is obtained, regardless of the shape and/or materialthe structure is built of, a layer of material, such as an elastomer,can be applied upon this original structure to produce a negative or amold of the original structure, which layer of material fills the cavityof the original structure. In addition, a sacrificial mold structure canbe obtained by applying a solvent soluble material over a replicatedelastomer structure. An example for such a solvent soluble material isPVA.

The inclined post can be in a vertical position, as exemplified in FIG.3, or in horizontal position, as exemplified in FIG. 15 (A). It shouldbe appreciated that, in certain cases, one inclined structure isrequired to create a sharp edge or tip, as exemplified in FIG. 15(B)(b). In some other cases, at least two inclined structures are neededto form a cutting edge of a blade, as exemplified in FIG. 15 (B)(a).

A blade or needle mold structure can be built by depositing a layer ofphotoresist, such as SU-8, on the inclined post. The thickness of thislayer defines the length (height) of the needle or blade. Therefore, thethickness of this layer of photoresist may be adjusted to obtain aneedle or blade of desired height. This layer of photoresist can bepatterned with UV exposures, resulting in a well with a post inside thewell. FIG. 3 (g) shows an example of patterning of a photoresistmaterial with UV exposure. The well and the post provided by this layerof photoresist are exemplified in FIG. 3 (h). The post provided by thislayer will become a part of the hollow section of a needle. The wellprovided by this layer defines the needle wall. It is to be noted thatpatterning of this layer of photoresist material can create a well ofvarious shapes or sizes, thus providing a needle with a wall of variousshapes or thickness. Also, patterning of this layer can create a needlewith variously shaped post, thus creating variously shaped hollowsection, although a needle with a cylindrical hollow section ispreferred and practical. Such patterning techniques to create a well anda post of various sizes or shapes are well known in the art oflithography. Prior to UV irradiation, this layer of photoresist may besoft-baked.

Consequently, a layer of photoresist material, such as SU-8, isdeposited upon the well with a post inside, which post defines thehollow section of the needle and which well defines the needle wall.This layer of photoresist can be patterned resulting in an extended postin the well, and creating a base for the needle. An example of creatingthe extended post and the needle base is illustrated in FIGS. 3 (i) and(j). This layer of photoresist may be soft-baked prior to UV irradiationand/or baked after UV irradiation. Then a development step is performedto obtain a mold structure, namely, a well with a (extended) post insidethe well.

Appropriate materials can be deposited upon a mold structure to form aneedle or a blade. Such materials may be metal, such as nickel,palladium, stainless steel, and/or other materials such as polymers andceramics. The mold structure can be removed to obtain the needle.Deposition of a metal upon a mold structure can be carried out byelectroplating. Prior to electroplating, a seed layer may be depositedonto a mold structure. After electroplating, chemical polishing may beused to remove access electroplated material. An example of depositing aseed layer, electroplating and opening the needle base is illustrated inFIG. 3 (k) through (m).

It is to be noted that a person skilled in the art can makemodifications to the methods as described. For example, a person skilledin the art can make modifications to the disclosed mold structure thusfabricate a mold structure comprising a well without a post inside.Applying a material upon the mold structure results in a needle withouta hollow section, or a blade. For another example, a blade of anarbitrary shape, such as a die cutter, can be created following similarprinciple and/or procedures. As well, the sequences of the procedures invarious embodiments of the invention can be changed. It is also to benoted that the method described can provide an array of inclinedstructures, thus providing a needle or blade array mold structure, andthus providing a needle array, a microneedle array, a blade array or amicroblade array.

It will be appreciated that a process for producing a needle or bladestructure may comprise a process of creating a mold structure. Forexample, in FIG. 3, the process for creating a needle mold comprisessteps (a) through (k). Consequently steps (l) and (m) produces a needlestructure built upon the mold. However, once a needle structure isobtained, a negative mold can be easily built by applying a layer ofmaterial, such as elastomer, over the needle or blade structure. Anexample of such elastomer is PDMS. Obtaining a mold structure byapplying an elastomer over an actual needle structure is exemplified inFIG. 13.

In another aspect, the invention provides a mold structure thatfacilitates fabrication of a needle, a needle array, a blade or a bladearray. Such a mold structure can be built by various embodiments of themethod disclosed. In one embodiment, a mold structure is built upon atleast one inclined structure, which controls the angle of the needle orblade tip. A needle mold may comprise a well with a post inside thewell, which well defines a part of the needle wall, and which postdefines a part of the hollow section of the needle. A specific exampleof a needle mold is illustrated in FIG. 3 (h) through (j). The need orblade mold provided by the present invention should be deemed moregeneral than illustrated in FIG. 3 (h) through (j). A blade or needlemold structure may comprise a well without a post inside, which welldefines part of the blade or needle body.

In certain embodiments, provided are devices including needles, blades,needle arrays, microneedle arrays, blade arrays and microblade arrays,wherein the angle or sharpness of the blade or needle are controlled byat least one inclined structure. A device provided herein can be of anysize, in either length or diameter. By varying the patterning ofexposures, devices of various shapes can be obtained. Various materials,such as metal, plastic, polymer, and/or biocompatible materials, can bedeposited onto a mold structure to create a needle or a blade for aspecific application. The devices can be used in drug delivery, samplecollection, surgical settings and other areas. Microneedles (ormicropipettes) can be used as a component in biomedical diagnosticdevices for drug delivery, blood extraction, or transport. Microbladescan be used in surgical devices that require micro-scale blade. Arraysof microneedles or microblades can be used for high throughput screeningor diagnostic assays, and other far reaching yet not foreseeableapplications.

The present invention is further described in the following non-limitingexamples, which are offered by way of illustration and are not intendedto limit the invention in any manner.

EXAMPLES Example 1 Creation of Sharp Metallic Microneedles andMicroneedle Arrays

A new manufacturing method to create a beveled metallic microneedle isintroduced. The method uses a side wall surface of an angled post as abase for the needle tip to create the beveled tip geometry for easy skinpenetration. With proper dimensional corrections, the microneedlemanufactured using the present method allows to keep the strength of theneedle structure while increasing skin penetration ability since thecross-section area of the needle post structure is not required tosacrifice. Therefore, the microneedle provided by the present method canbe used in clinical practice providing a safe and painlessadministration, but without potential concerns.

Construction of angled structures using inclined exposure fabricationtechnique is available for many applications, e.g., microfilter,microchannel, microstructures, etc.^([16-23]) The first fabrication stepfor a microneedle was performed with backside exposure on a layer ofSU-8. On a patterned metal layer coated on a glass substrate, SU-8 wasapplied and exposed from the back to create inclined post. The angle ofthe post is then used to determine the angle of the microneedlestructure. Since the UV light travels through air, glass, and SU-8 insequence, the range of the angle governed by Snell's law as below.

$\frac{\sin \; \theta_{1}}{n_{2}} = \frac{\sin \; \theta_{2}}{n_{1}}$

Where, Θ₁ and Θ₂ are the incident and refractive angles, respectively,n₁ and n₂ are the refractive index of the medium where the light isentering and leaving, respectively. According to Snell's law, theincident angle of the UV light that travels through the SU-8 layer isdetermined by the refraction index of the glass substrate. To determinethe incident angle of the light at the interface between SU-8 and theglass substrate, the refraction index used for the glass and SU-8 wereapproximately 1.52 and 1.67 at 365 nm wave lengths, respectively. Fromthis, the range of the refracted light that can be used to define thebeveled angle on the tip of the microneedle should be about between 0 to36.78 degrees. FIG. 1 shows the paths of the light traveled through theall three mediums and Table 1 shows the range of angles for the beveledmicroneedle tip that can be obtained from SU-8 in every 10 degrees ofincident angles of air. The calculated angles for the glass are used forincident light angles of the SU-8. FIG. 2 shows the actual skewed postfabricated during the microneedle manufacturing.

TABLE 1 Approximate beveled angle range of the microneedle air* glass*SU8* 0 0 0 10 6.55991952 5.9684576 20 13.0036574 11.817937 30 19.204897517.421641 40 25.0169643 22.637704 50 30.2634408 27.303849 60 34.733042231.236921 70 38.1861803 34.242047 80 40.3834451 36.136094 90 41.139510436.784174 *Angles in degreesRefractive index for air, glass, and SU-8 is 1, 1.52, and 1.67,respectively.

Therefore, patterning of any tube geometries on top of the side wallsurface of the inclined post which faces upward allows creating abeveled surface on the bottom of the microneedle mold structure. Thisbottom surface later becomes the beveled surface of the microneedlestructure.

The fabrication procedures to create an out of plane metallic beveledmicroneedle are illustrated in FIG. 3. There are four major microneedlemanufacturing stages. FIG. 3 (a) to (f) shows the first manufacturingstage described as following. The manufacture begins as performing ametal layer deposition, Chromium (Cr), of about 0.1 μm on a limestoneglass substrate using a Denton discovery 18 sputtering system. Apositive photoresist (AZ 1518) is then spun onto the metal layer forpatterning square arrays after baking and exposing it under the UltraViolet (UV) light. Developing patterned photoresist followed by etchingthe metal layer defines a mask to be used for creating the array ofskewed posts. SU-8 (2075), a negative photoresist, is then spin-coatedon the patterned metal layer at 500 rpm with acceleration of 100 rpm/sfor 10 seconds followed by spinning at 1200 rpm with acceleration of 300rmp/s for 30 seconds to obtain about 150 μm in thickness. Next, thesubstrate is soft-baked on a hotplate at 65° C. for 3 minutes followedby baking at 95° C. for 22.5 minutes. After cooling it down to the roomtemperature, the backside of the substrate is exposed under UV lightwith a dose of about 400 mJ/cm² at a tilted angle of 55 degrees usingKasper Instruments mask aligner. A post exposure bake is performed at65° C. for 3 minutes and 95° C. for 15 minutes. The SU-8 layer isdeveloped in a bath with a stirrer spinning at 700 rpm to enhancedeveloping rate for 25 minutes. The SU-8 layer is rinsed withisopropylalcohol (IPA) to check the degrees of development and removeuncrosslinked photoresist. The substrate is dried with a nitrogen gas toprepare for the next manufacturing steps of which the microneedlestructures will build on top of the array of the skewed posts (FIG. 3(g) to FIG. 3 (i)). The second layer of SU-8 is then carried out tospin-coat over the skewed post arrays at 300 rpm with acceleration of100 rpm for 10 seconds and spin at 630 rpm with acceleration of 500rpm/s for 30 seconds to obtain about 270 μm in thickness. FIG. 3 (g)shows the cross-section of the patterned geometry in which thedimensions of the outside and inside diameter of 370 μm and 70 μm,respectively, were used for the current experiment. It is noted that thethickness of this layer becomes the length of the microneedle. Thissecond SU-8 layer is soft-baked on the hotplate at 65° C. for 3 minutesand 95° C. for 5 hours and patterned with arrays of wells with a post inthe middle in each well using Electronic Visions EV-420 with a dose of550 mJ/cm². An example of how the post looks like inside of the well canbe seen in FIG. 4. FIG. 4 shows that the configuration of the interfacebetween the angled surface and the cylindrical post, which post will beused for creating the hollow section of the microneedle. Now, the thirdmanufacturing step (FIG. 3 (j) to (k)) starts without post-exposurebaking the second SU-8 layer, but spin-coating the third SU-8 layer overthe third layer at 500 rpm for 10 seconds and 1600 rpm to obtain 100 μm.The purpose of this step is to extend the post in the middle of the wellas well as to define the base for the entire 5×5 microneedle array.Soft-bake of the third layer on a hotplate results in the second SU-8layer becoming cross-linked in addition to removing solvents from thethird layer. Exposing the layer with a dose of 350 mJ/cm² and post-bakeare performed to cross-link the polymer layer at 65° C. for 3 minutesand 95° C. for 22.5 minutes. Next step is to develop the second andthird layers for 1 hour in the bath with a stirrer rotating at 700 rpm.FIG. 5 shows an array of wells with a post in the middle of each wellcreated after development. Finally, the last manufacturing step is tocreate the metallic microneedle array (FIG. 3 (l) to (m)). The array ofwells is subject to sputter to deposit a seed layer for electroplating.Nickel sulfamate bath is then prepared for nickel electroplating todeposit nickel about 500 μm thick. A selection of metal includesbiocompatible materials such as palladium, stainless steel, etc. inpractice. After nickel electroplating, Chemical Mechanical Polishing(CMP) is carried out to remove access material on the top surface of thenickel until SU-8 posts are exposed. FIG. 6 shows the picture of theprotruded SU-8 posts inside of the microneedle base during theelectroplating process. Removing the mold structure made of SU-8 is thefinal step to obtain a beveled metallic microneedle.

The most critical aspect of creating a microneedle with the proposeddesign method depends on the results from the lithography to create SU-8mold geometry for electroplating. Especially, the sharpness of theneedle tip is determined by how well SU-8 is developed and thus creatingfine corner geometry. The final product of a microneedle arrayfabricated using the proposed manufacturing method after removing SU-8layers are shown in FIGS. 7 and 8. The microneedle structures made ofnickel in these pictures are formed with round post mold geometry. Thetip angle shown in the figures is about 35° although the edges of thetip looks like somewhat rounded. The roundness is due to the tipgeometry in the bottom of the SU-8 mold which was not well developed.Moreover, the surface of the microneedle array is neither clean norsmooth. The uncleanness and roughness come from the left over of SU-8particles and craze of SU-8 mold surface resulted from the thermalstress during the curing of SU-8 polymer layer.

FIG. 9 shows the microneedle array with a flat tip surface resulted frommisalignment during the lithography process. Since the proposedmanufacturing method requires three SU-8 layers to complete the moldingprocess, the alignment of each layer determines the quality of finalproduct.

An angled view of microneedle with round post can be seen in FIG. 10 andbackside of its needle post can be seen in FIG. 11.

The advantage of using the new manufacturing method for creating amicroneedle is that it gives the freedom of changing the angle of theneedle tip in microneedle design without scarifying the needle poststrength for easy skin penetration. In addition, there is a potentialuse of the proposed manufacturing method such that various needle tipgeometries can be achieved with multiple exposures during thefabrication of the skewed post.

Example 2 Design of Microneedles and Microneedle Arrays

Microneedles and microneedle arrays can also be designed as shown inFIG. 13. A substrate is spin-coated with a layer of photoresist,softbaked and exposed to a light source. After post exposure bake, thephotoresist is developed resulting in an inclined post that defines theneedle tip. Another layer of photoresist is spin-coated, softbaked andpartially exposed to create a base and a post that defines the hollowsection of a needle. The photoresist is partially developed to exposethe base and the post that defines the hollow section of the needle. Thephotoresist is exposed partially to the light source to createboundaries of the needle structure. After post exposure bake, the entiremold structure is developed. A seed layer is deposited onto the moldstructure and a metal layer is electroplated. Alternatively, the seedlayer may be deposited right after the inclined post is created.Chemical mechanical polishing opens the hollow area of the needle. Themold structure is removed to obtain the final needle structure. A layerof elastomer, e.g., PDMS, is cast over the actual needle structure andtherefore, a mold made of PDMS is obtained.

Example 3 Design of Tapered Microneedles and Microneedle Arrays

Tapered microneedles and microneedle arrays can be created as shown inFIG. 14. A negative photoresist is coated on a substrate, softbaked, andexposed under UV light with an inclined exposure. After post exposurebake and development, the photoresist is coated with a mold releaseagent or a sacrificial layer for easy release of an elastomer layer(e.g., PDMS). An example for such a mold release agent is afluorosilanizing agent. An elastomer is cast upon the mold release agentor the sacrificial layer to obtain an elastomer structure, which is thenused as a base for further construction.

The elastomer base is coated with a layer of negative photoresist (e.g.,SU-8) for creating a needle or needle array mold structure. The negativephotoresist is softbaked and exposed with a given photomask positionedon the negative photoresist. To create tapered geometry, a gray scalemask can be used. Alternatively, adjusting diffraction of the light canalso produce similar geometry.

Another layer of SU-8 is spin-coated without developing the previouslayer. The entire layers are softbaked, exposed and post exposure baked.Alternatively, calculated dosage can be used for exposing only thesecond SU-8 layer. Development of the layers results in a SU-8 moldstructure. A layer of material, such as metal, can be cast upon the moldstructure and therefore produce an actual needle structure.

This example shows that a replicated angled structure, such as the onemade of PDMS, can be used a base for fabricating a microneedle.

Example 4 Design of a Die Cutter

A die cutter can be created as shown in FIG. 16. A photoresist layer isspin-coated on a substrate. Point light sources, such as laser, writedirectly on the photoresist at a defined angle. An arbitrary inclinedshaped structure is obtained after developing the photoresist. A layerof photoresist is spin-coated on the arbitrary shaped structure. Theblade 2D top layout is patterned using a mask or by direct writing.After the photoresist is developed, the cavity can be filled with amaterial such as ceramics. Removal of the photoresist mold to obtain adie cutter. A metal cutter can also be obtained by electroplating.

While this invention has been described in certain embodiments, thepresent invention can be further modified within the spirit and scope ofthis disclosure. This application is therefore intended to cover anyvariations, uses, or adaptations of the invention using its generalprinciples. Further, this application is intended to cover suchdepartures from the present disclosure as come within known or customarypractice in the art to which this invention pertains and which fallwithin the limits of the appended claims.

All references, including publications, patents, and patentapplications, cited herein are hereby incorporated by reference to thesame extent as if each reference were individually and specificallyindicated to be incorporated by reference and were set forth in itsentirety herein. The references discussed herein are provided solely fortheir disclosure prior to the filing date of the present application.Nothing herein is to be construed as an admission that the inventors arenot entitled to antedate such disclosure by virtue of prior invention.

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What is claimed is:
 1. An implement, the implement prepared by: creatingat least one inclined structure which defines an angle of an angled tipof the implement, the angle defining the implement's sharpness; andbuilding at least one needle mold structure or at least one blade moldstructure on the inclined structure.
 2. The implement of claim 1,wherein the at least one inclined structure is created by one or more ofmechanical machining, laser ablation, lithography, abrasion, electricdischarged machining (EDM), electric chemical machining (ECM), etching,or deposition.
 3. The implement of claim 1, wherein building the leastone needle mold structure or at least one blade mold structure on theinclined structure comprises building a microneedle array mold structureincluding a plurality of needle mold structures on the inclinedstructure, and wherein the implement is combined with one or more otherimplements to from a microneedle array with a controllable beveled angleneedle tip, the angle of the controllable beveled angle needle tip beingcontrolled by the inclined structure.
 4. A method for making a moldstructure for an implement, the method comprising: applying an elastomerover an implement, the implement prepared by: creating at least oneinclined structure which defines an angle of an angled tip of theimplement, the angle defining the implement's sharpness; and building atleast one needle mold structure or at least one blade mold structure onthe inclined structure; and removing the implement to obtain theelastomer mold structure.
 5. The method according to claim 4, whereinthe elastomer is PDMS.
 6. The method according to claim 4, furthercomprising: applying an elastomer over the mold structure to obtain anelastomer structure; disassociating the elastomer structure from themold structure; applying a solvent soluble material over the elastomerstructure; and removing the elastomer structure to obtain a soluble moldstructure.
 7. The method according to claim 6, wherein the solventsoluble material is PVA.
 8. A mold structure, the mold structureprepared by: applying an elastomer over an implement, the implementprepared by: creating at least one inclined structure which defines anangle of an angled tip of the implement, the angle defining theimplement's sharpness; and building at least one needle mold structureor at least one blade mold structure on the inclined structure; andremoving the implement to obtain the elastomer mold structure.